Ras signalling regulates differentiation and UCP1 expression in models of brown adipogenesis

The Ras/Raf/MEK/ERK pathway has been recognised as an important signalling module in adipogenesis and adipocyte function, but whether it promotes or inhibits the formation of fat cells has not been reconciled.

Here we investigate the significance of Ras signalling intensity on two unrelated models of mouse brown adipocyte differentiation.

A constitutively active H-Ras mutant (Ras V12) caused a complete block of adipose conversion, as manifested by a lack of both lipid accumulation and induction of adipocyte gene expression. The Ras V12-mediated impediment of differentiation was inefficiently rescued by forced expression of the adipogenic transcription factors C/EBPalpha and PPARgamma. However, the defective differentiation was alleviated by MEK inhibitors, suggesting that the obstruction of differentiation was dependent on activation of ERK. A dominant interfering H-Ras mutant (Ras N17) did not inhibit differentiation, but led to increased expression of genes important for energy dissipation in brown fat cells, including UCP1.

These data suggest that the intensity of Ras signalling is important for differentiation and UCP1 expression in models of brown adipogenesis.